Cholesterol “win” does Ionis and Pfizer a fat lot of good

Investors were unconvinced by yesterday’s apparent mid-stage success with Ionis and Pfizer’s cholesterol-lowering project vupanorsen. On the face of it the anti-ANGPTL3 antisense did what it needed to do in the dose-ranging Translate Timi 70 trial, statistically lowering non-HDL cholesterol at all doses tested versus placebo at week 24. However, Pfizer’s commitment to the asset is far from clear: the big pharma left Ionis to report the results, and also seemed lukewarm about further development, only saying it was reviewing the findings before determining next steps. In another potential red flag, the study found liver enzyme elevations, primarily at the highest doses tested, as well as increases in hepatic fat fraction at “certain doses”. Ionis said there were no Hy’s law cases. More information is needed, but there must now be fears that the group might not be able to find a therapeutic window for vupanorsen; Ionis’s stock sank 2% yesterday and another 2% after hours. The liver findings could also throw doubt on ANGPTL3 as a target. However, the pivotal trial of Regeneron’s Evkeeza in homozygous familial hypercholesterolaemia was not marked by liver enzyme worries, something that could provide solace to other developers of anti-ANGPTL3 projects, though of course Evkeeza is a MAb, unlike the other projects in this space. 

ANGPTL3 modulators in clinical development for cardiometabolic indications
Project Company Description Indication  Trial details
Evkeeza (evinacumab) Regeneron Anti-ANGPTL3 MAb HoFH Elipse, 49-point reduction in LDL-C vs SOC 
Phase 2
Vupanorsen (AKCEA-ANGPTL3-LRx/ PF-07285557) Ionis/Pfizer ANGPTL3 antisense oligonucleotide Dyslipidaemias Translate Timi 70, "statistically significant" reduction with all dose vs placebo at week 24
ARO-ANG3 Arrowhead Anti-ANGPTL3 RNAi therapeutic Dyslipidaemias Arches-2, completes Oct 2022
Phase 1
LY3561774 Lilly/Novo (Dicerna) Anti-ANGPTL3 small interfering RNA Dyslipidaemias NCT04644809, completes Apr 2022
HoFH=homozygous familial hypercholesterolaemia. Source: Evaluate Pharma &

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